The mammalian somatosensory system detects a wide variety of mechanical stimuli, such as texture, shape, vibration or pressure. This variety of stimuli is matched by a diverse array of mechanosensitive somatosensory neurons. Non-neuronal cells in the skin, such as keratinocytes, may also coordinate with sensory neurons to transduce force. The goal of this proposal is to identify molecular and cellular mechanisms underlying somatosensory mechanotransduction. We hypothesize that both primary afferent somatosensory neurons and keratinocytes mediate mechanosensitive responses in the skin. We will use a variety of techniques including live-cell Ca2+ imaging, electrophysiology and pharmacology to characterize transduction channels in sensory neurons and keratinocytes. We will then probe the role of candidate channels in vivo. The proposed experiments will answer fundamental questions about somatosensory mechanotransduction, including: 1) What are the molecular identities of the ion channels that transduce touch in sensory neurons and keratinocytes? and 2) How does touch-evoked signaling in keratinocytes alter primary afferent neuron function? PUBLIC HEALTH RELEVANCE: Though unpleasant, pain warns us against harmful stimuli in the environment and evokes protective reflexes. But pain can also be a chronic, debilitating affliction that no longer serves a protective purpose. Chronic pain not only occurs after trauma-induced inflammation and tissue injury, but also results from many diseases;pain is the major complaint of patients suffering from cancer, AIDS, and diabetes. Understanding the mechanisms that evoke acute and chronic pain may lead to the development of much needed, novel drugs and therapies to alleviate pain.